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Bi-allelic loss-of-...
Bi-allelic loss-of-function variants in PPFIBP1 cause a neurodevelopmental disorder with microcephaly, epilepsy, and periventricular calcifications
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- Rosenhahn, Erik (författare)
- Institute of Human Genetics, University of Leipzig Medical Center, Germany
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- O'Brien, Thomas J. (författare)
- MRC London Institute of Medical Sciences, United Kingdom
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- Zaki, Maha S. (författare)
- Clinical Genetics Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo, Egypt
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- Sorge, Ina (författare)
- Department of Pediatric Radiology, University Hospital Leipzig, Germany
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- Wieczorek, Dagmar (författare)
- Institute of Human Genetics, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Germany
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- Rostasy, Kevin (författare)
- Department of Pediatric Neurology, Children's and Adolescents’ Hospital Datteln, Witten/Herdecke University, Germany
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- Vitobello, Antonio (författare)
- UF6254 Innovation en Diagnostic Genomique des Maladies Rares, CHU Dijon Bourgogne, FHU translad, Génétique des Anomalies du Développement, INSERM UMR 1231, Université de Bourgogne-Franche Comté, Dijon, France
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- Nambot, Sophie (författare)
- Centre de Génétique et Centre de référence des Maladies rare, Anomalies du Développement et Syndromes Malformatifs, Hôpital d'Enfants, Centre Hospitalier Universitaire de Dijon, France
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- Alkuraya, Fowsan S. (författare)
- Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia ; Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
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- Hashem, Mais O. (författare)
- Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
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- Alhashem, Amal (författare)
- Karolinska Institutet
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- Tabarki, Brahim (författare)
- Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia
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- Alamri, Abdullah S. (författare)
- Department of Pediatrics, Imam Abdulrahman bin Faisal University, Dammam, Saudi Arabia
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- Al Safar, Ayat H. (författare)
- Department of Pediatrics, Imam Abdulrahman bin Faisal University, Dammam, Saudi Arabia
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- Bubshait, Dalal K. (författare)
- Department of Pediatrics, Imam Abdulrahman bin Faisal University, Dammam, Saudi Arabia
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- Alahmady, Nada F. (författare)
- Biology Department, Imam Abdulrahman bin Faisal University, Dammam, Saudi Arabia
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- Gleeson, Joseph G. (författare)
- Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA ; Rady Children’s Institute for Genomic Medicine, San Diego, La Jolla, CA, USA
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- Abdel-Hamid, Mohamed S. (författare)
- Medical Molecular Genetics Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo, Egypt
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- Lesko, Nicole (författare)
- Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden ; Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden
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- Ygberg, Sofia (författare)
- Karolinska Institutet
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- Correia, Sandrina P. (författare)
- Karolinska Institutet
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- Wredenberg, Anna (författare)
- Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden ; Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden
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- Alavi, Shahryar (författare)
- Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Iran ; Palindrome, Isfahan, Iran
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- Seyedhassani, Seyed M. (författare)
- Dr. Seyedhassani Medical Genetic Center, Yazd, Iran
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- Ebrahimi Nasab, Mahya (författare)
- Dr. Seyedhassani Medical Genetic Center, Yazd, Iran
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- Hussien, Haytham (författare)
- Alexandria University Children’s Hospital, Faculty of Medicine, Alexandria University, Egypt
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- Omar, Tarek E. I. (författare)
- Alexandria University Children’s Hospital, Faculty of Medicine, Alexandria University, Egypt
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- Harzallah, Ines (författare)
- Clinical, Chromosomal and Molecular Genetics Department, University Hospital Center, Saint-Étienne, France
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- Touraine, Renaud (författare)
- Clinical, Chromosomal and Molecular Genetics Department, University Hospital Center, Saint-Étienne, France
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- Tajsharghi, Homa (författare)
- Högskolan i Skövde,Institutionen för hälsovetenskaper,Forskningsmiljön hälsa, hållbarhet och digitalisering,Translationell medicin TRIM, Translational Medicine
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- Morsy, Heba (författare)
- UCL Queen Square Institute of Neurology, University College London, UK
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- Houlden, Henry (författare)
- UCL Queen Square Institute of Neurology, University College London, UK
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- Shahrooei, Mohammad (författare)
- Specialized Immunology Laboratory of Dr. Shahrooei, Sina Medical Complex, Ahvaz, Iran ; Department of Microbiology and Immunology, Clinical and Diagnostic Immunology, KU Leuven, Belgium
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- Ghavideldarestani, Maryam (författare)
- Specialized Immunology Laboratory of Dr. Shahrooei, Sina Medical Complex, Ahvaz, Iran
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- Abdel-Salam, Ghada M. H. (författare)
- Clinical Genetics Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo, Egypt
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- Torella, Annalaura (författare)
- Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples, Italy ; Telethon Institute of Genetics and Medicine, Naples, Italy
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- Zanobio, Mariateresa (författare)
- Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples, Italy
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- Terrone, Gaetano (författare)
- Child Neurology Unit, Department of Translational Medical Science, University of Naples Federico II, Naples, Italy
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- Brunetti-Pierri, Nicola (författare)
- Telethon Institute of Genetics and Medicine, Naples, Italy ; Department of Translational Medicine, Section of Pediatrics, University of Naples Federico II, Italy
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- Omrani, Abdolmajid (författare)
- Division of Clinical Studies, The Persian Gulf Nuclear Medicine Research Center, Bushehr University of Medical Sciences, Iran
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- Hentschel, Julia (författare)
- Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany
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- Lemke, Johannes R. (författare)
- Institute of Human Genetics, University of Leipzig Medical Center, Germany ; Center for Rare Diseases, University of Leipzig Medical Center, Germany
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- Sticht, Heinrich (författare)
- Institute of Biochemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
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- Abou Jamra, Rami (författare)
- Institute of Human Genetics, University of Leipzig Medical Center, Germany
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- Brown, Andre E. X. (författare)
- MRC London Institute of Medical Sciences, UK ; Faculty of Medicine, Institute of Clinical Sciences, Imperial College London, UK ;
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- Maroofian, Reza (författare)
- UCL Queen Square Institute of Neurology, University College London, UK
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- Platzer, Konrad (författare)
- Institute of Human Genetics, University of Leipzig Medical Center, Germany
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(creator_code:org_t)
- Cell Press, 2022
- 2022
- Engelska.
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Ingår i: American Journal of Human Genetics. - : Cell Press. - 0002-9297 .- 1537-6605. ; 109:8, s. 1421-1435
- Relaterad länk:
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https://doi.org/10.1...
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https://his.diva-por... (primary) (Raw object)
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https://urn.kb.se/re...
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https://doi.org/10.1...
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http://kipublication...
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Abstract
Ämnesord
Stäng
- PPFIBP1 encodes for the liprin-β1 protein, which has been shown to play a role in neuronal outgrowth and synapse formation in Drosophila melanogaster. By exome and genome sequencing, we detected nine ultra-rare homozygous loss-of-function variants in 16 individuals from 12 unrelated families. The individuals presented with moderate to profound developmental delay, often refractory early-onset epilepsy, and progressive microcephaly. Further common clinical findings included muscular hyper- and hypotonia, spasticity, failure to thrive and short stature, feeding difficulties, impaired vision, and congenital heart defects. Neuroimaging revealed abnormalities of brain morphology with leukoencephalopathy, ventriculomegaly, cortical abnormalities, and intracranial periventricular calcifications as major features. In a fetus with intracranial calcifications, we identified a rare homozygous missense variant that by structural analysis was predicted to disturb the topology of the SAM domain region that is essential for protein-protein interaction. For further insight into the effects of PPFIBP1 loss of function, we performed automated behavioral phenotyping of a Caenorhabditis elegans PPFIBP1/hlb-1 knockout model, which revealed defects in spontaneous and light-induced behavior and confirmed resistance to the acetylcholinesterase inhibitor aldicarb, suggesting a defect in the neuronal presynaptic zone. In conclusion, we establish bi-allelic loss-of-function variants in PPFIBP1 as a cause of an autosomal recessive severe neurodevelopmental disorder with early-onset epilepsy, microcephaly, and periventricular calcifications.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Medicinsk genetik (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medical Genetics (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Klinisk laboratoriemedicin (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Clinical Laboratory Medicine (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Neurologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Neurology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinsk bioteknologi -- Biomedicinsk laboratorievetenskap/teknologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Medical Biotechnology -- Biomedical Laboratory Science/Technology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
Nyckelord
- Acetylcholinesterase
- Animals
- Drosophila melanogaster
- Epilepsy
- Loss of Heterozygosity
- Microcephaly
- Nervous System Malformations
- Neurodevelopmental Disorders
- Pedigree
- animal
- genetics
- heterozygosity loss
- mental disease
- nervous system malformation
- Translationell medicin TRIM
- Translational Medicine TRIM
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Rosenhahn, Erik
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O'Brien, Thomas ...
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Zaki, Maha S.
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Sorge, Ina
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Wieczorek, Dagma ...
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Rostasy, Kevin
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Vitobello, Anton ...
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Nambot, Sophie
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Alkuraya, Fowsan ...
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Hashem, Mais O.
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Alhashem, Amal
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Tabarki, Brahim
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Alamri, Abdullah ...
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Al Safar, Ayat H ...
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Bubshait, Dalal ...
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Alahmady, Nada F ...
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Gleeson, Joseph ...
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Abdel-Hamid, Moh ...
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Lesko, Nicole
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Ygberg, Sofia
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Correia, Sandrin ...
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Wredenberg, Anna
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Alavi, Shahryar
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Seyedhassani, Se ...
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Ebrahimi Nasab, ...
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Hussien, Haytham
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Omar, Tarek E. I ...
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Harzallah, Ines
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Touraine, Renaud
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Tajsharghi, Homa
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Morsy, Heba
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Houlden, Henry
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Shahrooei, Moham ...
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Zanobio, Mariate ...
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Terrone, Gaetano
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Omrani, Abdolmaj ...
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Hentschel, Julia
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Lemke, Johannes ...
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Sticht, Heinrich
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Abou Jamra, Rami
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Brown, Andre E. ...
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Maroofian, Reza
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Platzer, Konrad
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